The great majority of tobacco addiction begins during adolescence, but very little is known about the neurobehavioral effects of nicotine in adolescents compared to adults. Adolescents are still undergoing important neurodevelopmental changes on the path to adulthood. Nicotine exposure in adolescence may have lasting impacts on this late neurodevelopment. There are suggestions in the clinical literature that more heavily addicted smokers begin smoking earlier in adolescence, but the impact of nicotine self-administration during adolescence versus self-selection bias whereby people more prone to heavy addiction also begin earlier, cannot be ethically unconfounded in humans. This project is based on our hypothesis beginning nicotine self-administration during adolescence leads to greater nicotine intake and dependence than beginning in adulthood. Our preliminary data demonstrated in the rat model of nicotine self-administration that rats with adolescent-onset nicotine self-administration self-administer substantially higher total doses of nicotine than adult-onset rats, This higher rate of nicotine self-administration continues into adulthood with an approximate doubling of nicotine self-administration. [unreadable] [unreadable] The proposed experiments will determine the causal relationship between adolescent-onset nicotine self-administration and enhanced long-term nicotine self-administration with these Specific Aims. [unreadable] 1. Determine the pharmacokinetics and dose-effect functions of nicotine in adolescents and adult rats. [unreadable] 2. Determine the impact of nicotine replacement and nicotinic antagonist therapy on nicotine self-administration in adolescent-onset and adult-onset nicotine self-administration. [unreadable] 3. Determine the age threshold for the adult-like nicotine self-administration. [unreadable] 4. Determine if adolescent-onset nicotine self-administration enhances cocaine dependence. [unreadable] 5. Determine sex differences in adolescent-onset nicotine self-administration. Nicotine pharmacokinetic measurements in adolescent and adult rats will be used to determine the effect of altered distribution and metabolism versus pharmacodynamic factors in accounting for age-related differences in nicotine self-administration. [unreadable] [unreadable] Benefits of this research include a more relevant animal model of adolescent-onset smoking, improved understanding of how adolescent-onset nicotine use potentiates nicotine intake, a cause and effect determination of the gateway hypothesis of adolescent nicotine use leading to harder drugs and the development of better treatments for adolescent-onset nicotine dependence. [unreadable] [unreadable]